A substantial proportion of HIV-infected patients die within the first 6 months after initiating highly active antiretroviral therapy (HAART). Decreasing these early deaths has the potential to greatly improve outcomes in antiretroviral therapy scale-up efforts worldwide. However, responses to HAART among patients suffering early death are unclear, since previous studies have focused on pre-HAART risk factors or time-updated response factors that measure response after early deaths have occurred. Thus, a fundamental gap in existing knowledge of why some patients suffer early death remains. Given that our long-term goal is to decrease early deaths among adults treated with HAART, an observational cohort study specifically addressing mechanisms of early deaths is proposed. The finding that lower pre-treatment CD4+ T cell counts are associated with both delayed and pathologically rapid recovery of quantitative and qualitative measurements of cell mediated immunity after HAART initiation raises the fundamental question of whether or not the rate of cellular immune restoration relates to risk of early death after HAART initiation. In one scenario patients may be suffering early deaths via rapid immune recovery and severe or fatal immune reconstitution inflammatory syndrome (IRIS). In another scenario delayed recovery of cellular immunity may be associated with inability to control opportunistic pathogens and death. This proposal adopts an epidemiologic approach in order to examine the relationship between very early (i.e., within the first 4 weeks) virologic and immunologic responses and risk of early death after HAART initiation. These relationships will be examined in adults with advanced HIV infection (as indicated by a pre-HAART CD4 + T cell count < 100 cells/mm3) and active TB disease. We will conduct a prospective cohort study in Gaborone, Botswana to evaluate risk factors for death within the first 6 months after HAART initiation among these individuals, focusing first on the rate of recovery of Mycobacterium tuberculosis-specific cellular immunity in the first 4 weeks after HAART initiation. We will then proceed backwards along the classic causal pathway of response to HAART to determine if very early adherence and very early virologic responses are associated with early death in order to define specific interventions capable of preventing this outcome. Given that the majority of all deaths in the first year after HAART initiation occur in the first 6 months among patients with advanced HIV disease, this project has the potential to improve outcomes in global scale-up efforts. PUBLIC HEALTH RELEVANCE: This research proposal evaluates the relationship between very early response to HAART and risk of death in the first 6 months after HAART initiation among adults with advanced HIV disease and active tuberculosis (TB) disease, the most important opportunistic infection globally. Conducted as a prospective cohort study in Gaborone, Botswana, the project will yield important information to clinical care and public health efforts designed to improve the outcomes in global antiretroviral therapy scale-up efforts.